The purpose of this proposal is to define the mechanisms responsible for the induction of immunologic tolerance by the enteric presentation of antigen. Specific aims include using an in vitro culture system recently developed in our laboratory to further define the cells which mediate this form of tolerance (T suppressor cells) and the cellular targets of this suppression. This proposal will also investigate the molecular basis underlying this immunologic circuit by evaluating the properties of soluble mediators released by cloned T suppressor cell lines. An additional aim of this proposal is to evaluate the mechanism responsible for the resistance of autoimmune-prone NZB mice to tolerance induced by antigen feeding. Establishing a clear association between oral tolerance defects and clinically significant autoimmunity will influence concepts of the pathogenesis of autoimmune disease. A final goal is to evaluate the functional status of the mucosal immune system in spontaneously autoimmune mice; this would represent the first such study to date. Defects in the mucosal immune system may result in excessive stimulation by enteric derived antigens, loss of functional T suppressor activity, and the appearance or worsening of the clinical manifestations of autoimmunity. The long-range purposes of pursuing these aims are: 1) to improve our understanding of the role of the enteric immune system in maintaining immunologic homeostasis; and 2) to explore the possible connection between defects in enteric immune function and the manifestations of autoimmunity.